FDA label 94c0f2c2-7eb4-11e8-9bf0-90d39d46d017

WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH SMOKING, RISK OF VENOUS THROMBOEMBOLISM, and PHARMACOKINETIC PROFILE OF ETHINYL ESTRADIOL Cigarette Smoking and Serious Cardiovascular Risks Cigarette smoking increases the risk of serious cardiovascular events from hormonal contraceptive use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, hormonal contraceptives, including ORTHO EVRA, should not be used by women who are over 35 years of age and smoke. Risk of Venous Thromboembolism The risk of venous thromboembolism (VTE) among women aged 15–44 who used the ORTHO EVRA patch compared to women who used several different oral contraceptives was assessed in five U.S. epidemiologic studies using electronic healthcare claims data. The relative risk estimates ranged from 1.2 to 2.2; one of the studies found a statistically significant increased relative risk of VTE for current users of ORTHO EVRA [ see Warnings and Precautions (5.1) ] . Pharmacokinetic (PK) Profile of Ethinyl Estradiol (EE) The PK profile for the ORTHO EVRA patch is different from the PK profile for oral contraceptives in that it has a higher steady state concentrations and a lower peak concentration. Area under the time-concentration curve (AUC) and average concentration at steady state (C ss ) for EE are approximately 60% higher in women using ORTHO EVRA compared with women using an oral contraceptive containing 35 mcg of EE. In contrast, the peak concentration (C max ) for EE is approximately 25% lower in women using ORTHO EVRA. It is not known whether there are changes in the risk of serious adverse events based on the differences in PK profiles of EE in women using ORTHO EVRA compared with women using oral contraceptives containing 30–35 mcg of EE. Increased estrogen exposure may increase the risk of adverse events, including VTE [ see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ]. WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH SMOKING, RISK OF VENOUS THROMBOEMBOLISM, and PHARMACOKINETIC PROFILE OF ETHINYL ESTRADIOL See full prescribing information for complete boxed warning. Women over 35 years old who smoke should not use ORTHO EVRA. ( 4 ) Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptives (CHC) use. ( 4 ) There may be an increased risk of venous thromboembolism (VTE) among women who use the ORTHO EVRA patch compared to women who use certain oral contraceptives. ( 5.1 ) The pharmacokinetic (PK) profile of ethinyl estradiol (EE) for the ORTHO EVRA patch is different from the PK profile for oral contraceptives in that it has higher area under the time-concentration curve, steady state concentrations and lower peak concentrations. ( 5.2 )

5 WARNINGS AND PRECAUTIONS Vascular risks: Stop ORTHO EVRA if a thrombotic event occurs. Stop at least 4 weeks before and through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breastfeeding. ( 5.1 ) Liver disease: Discontinue ORTHO EVRA if jaundice occurs. ( 5.3 ) High blood pressure: Do not prescribe ORTHO EVRA for women with uncontrolled hypertension or hypertension with vascular disease. ( 5.5 ) Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking ORTHO EVRA. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. ( 5.7 ) Headache: Evaluate significant change in headaches and discontinue ORTHO EVRA if indicated. ( 5.8 ) Uterine bleeding: Evaluate irregular bleeding or amenorrhea. ( 5.9 ) 5.1 Thromboembolic Disorders and Other Vascular Problems Stop ORTHO EVRA if an arterial or deep venous thrombotic event (VTE) occurs. Stop ORTHO EVRA if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. If feasible, stop ORTHO EVRA at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE. Discontinue use of ORTHO EVRA during prolonged immobilization and resume treatment based on clinical judgment. Start ORTHO EVRA no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum VTE decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. The use of combination hormonal contraceptives (CHCs) increases the risk of VTE. Known risk factors for VTE include smoking, obesity and family history of VTE, in addition to other factors that contraindicate use of CHCs [see Contraindications (4) ] . Five epidemiologic studies 1–9 that assessed the risk of VTE associated with use of ORTHO EVRA are described below. These are 4 case control studies, that compared VTE rates among women using ORTHO EVRA to rates among women using an OC comparator, and an FDA-funded cohort study that estimated and compared VTE rates among women using various hormonal contraceptives, including ORTHO EVRA. All five studies were retrospective studies from U.S. electronic healthcare databases and included women aged 15–44 (10–55 in the FDA-funded study) who used ORTHO EVRA or oral contraceptives containing 20–35 mcg of ethinyl estradiol (EE) and levonorgestrel (LNG), norethindrone, or norgestimate (NGM). NGM is the prodrug for NGMN, the progestin in ORTHO EVRA. Some of the data from the epidemiologic studies suggest an increased risk of VTE with use of ORTHO EVRA compared to use of some combined oral contraceptives (see Table 1 ). The studies used slightly different designs and reported relative risk estimates ranging from 1.2 to 2.2. None of the studies have adjusted for body mass index, smoking, and family history of VTE, which are potential confounders. The interpretations of these relative risk estimates range from no increase in risk to an approximate doubling of risk. One of the studies found a statistically significant increased risk of VTE for current users of ORTHO EVRA. The five studies are: The i3 Ingenix study with NGM-containing oral contraceptives as the comparator, including a 24-month extension, based on the Ingenix Research Datamart; this study included patient chart review to confirm the VTE occurrence. The Boston Collaborative Drug Surveillance Program (BCDSP) with NGM-containing oral contraceptives as the comparator (BCDSP NGM), including two extensions of 17 and 14 months, respectively, based on the Pharmetrics database, using only non-fatal idiopathic cases. VTE cases were not confirmed by chart review. BCDSP with LNG-containing oral contraceptives as the comparator, based on the Pharmetrics database, using only non-fatal idiopathic cases. VTE cases were not confirmed by chart review. BCDSP with LNG-containing oral contraceptives as the comparator, based on the Marketscan database, using only non-fatal idiopathic cases. VTE cases were not confirmed by chart review. FDA-funded study with two groups of comparators [1) LNG-containing oral contraceptives, and 2) oral contraceptives that contain LNG, norethindrone or norgestimate], based on Kaiser Permanente and Medicaid databases. This study used all cases of VTE (idiopathic and non-idiopathic) and included patient chart review to confirm the VTE occurrence. The i3 Ingenix and BCDSP NGM studies have provided data on additional cases identified in study extensions; however, each study extension was not powered to provide independent estimates of risk. The pooled estimates provide the most reliable estimates of VTE risk. Risk ratios from the original and various extensions of the i3 Ingenix and BCDSP NGM studies are provided in Table 1. The results of these studies are presented in Figure 1. Table 1: Estimates (Risk Ratios) of Venous Thromboembolism Risk in Current Users of ORTHO EVRA Compared to Combined Oral Contraceptive Users Epidemiologic Study "New users" – i.e., women with no prior exposure to the drug studied during a pre-specified time period – are considered to be the most informative population to study in pharmacoepidemiologic safety studies. All estimates took account of new-user status. The method and time period used to identify "new users" varied from study to study. Comparator Product Risk Ratios (95% CI) i3 Ingenix NGM Study in Ingenix Research Datamart 1,6,7,8 NGM/35 mcg EE NGM = norgestimate; EE = ethinyl estradiol 2.2 Increase in risk of VTE is statistically significant (1.2–4.0) Pooled risk ratio from references 1 and 6 covering the initial 33-month study plus 24-month extension. [Initial 33 months of data: Risk Ratio (95% CI) = 2.5 C (1.1–5.5); Separate estimate from the 24 months of data on new cases not included in the previous estimate: Risk Ratio (95% CI) = 1.4 (0.5–3.7)]. These risk ratios are based on idiopathic cases (those in women without other known risk factors for VTE). If all VTE cases are considered, the pooled risk ratio and 95% CI are 2.0 (1.2–3.3) C . BCDSP BCDSP = Boston Collaborative Drug Surveillance Program; the risk ratios are based on idiopathic cases. NGM Study in Pharmetrics database 2,3,5 NGM/35 mcg EE 1.2 (0.9–1.8) Pooled risk ratio from references 2, 3 and 5 covering the initial 36-month study, plus 17-month and 14-month extensions. [Initial 36 months of data: Risk Ratio (95% CI) = 0.9 (0.5–1.6); Separate estimate from 17 months of data on new cases not included in the previous estimate: Risk Ratio (95% CI) = 1.1 (0.6–2.1); Separate estimate from 14 months of data on new cases not included in the previous estimates: Risk Ratio (95% CI) = 2.4 C (1.2–5.0)] BCDSP LNG Study in Pharmetrics database 4 LNG LNG = levonorgestrel /30 mcg EE 2.0 (0.9–4.1) 48 months of data. BCDSP LNG Study in Marketscan database 4 LNG/30 mcg EE 1.3 (0.8–2.1) 69 months of data. FDA-funded Study in Kaiser Permanente and Medicaid databases 84 months of data in FDA-funded study , Results for "All users," i.e., initiation and continuing use of study combination hormonal contraception: "All progestins"/20–35 mcg EE, Risk Ratio (95% CI) = 1.6 (1.2–2.1) C and LNG/30 mcg EE, Risk Ratio (95% CI) = 1.3 (1.0–1.8). , 9 "All progestins Includes the following progestins: LNG, norethindrone, norgestimate. "/20–35 mcg EE 1.4 (0.9–2.0) LNG/ 30 mcg EE 1.2 (0.8–1.9) Figure 1: VTE Risk of ORTHO EVRA Relative to Combined Oral Contraceptives a All estimates took account of new-user status. The method and time period used to identify "new users" varied from study to study. b Includes the following progestins: levonorgestrel (LNG), norethindrone, norgestimate (NGM). BCDSP = Boston Collaborative Drug Surveillance Program EE = ethinyl estradiol An increased risk of thromboembolic and thrombotic disease associated with the use of combination hormonal contraceptives (CHCs) is well established. Although the absolute VTE rates are increased for users of CHCs compared to non-users, the rates associated with pregnancy are even greater, especially during the post-partum period (see Figure 2 ). The frequency of VTE in women using CHCs has been estimated to be 3 to 12 cases per 10,000 woman-years. The risk of VTE is highest during the first year of use of CHCs and when restarting hormonal contraception after a break of 4 weeks or longer. The risk of thromboembolic disease due to CHCs gradually disappears after CHC use is discontinued. Figure 2 shows the risk of developing a VTE for women who are not pregnant and do not use CHCs, for women who use CHCs, for pregnant women, and for women in the post-partum period. To put the risk of developing a VTE into perspective: If 10,000 women who are not pregnant and do not use CHCs are followed for one year, between 1 and 5 of these women will develop a VTE. Figure 2: Likelihood of Developing a VTE *CHC = combination hormonal contraception **Pregnancy data based on actual duration of pregnancy in the reference studies. Based on a model assumption that pregnancy duration is nine months, the rate is 7 to 27 per 10,000 WY. Use of CHCs also increases the risk of arterial thromboses such as, cerebrovascular events (thrombotic and hemorrhagic strokes) and myocardial infarctions, especially in women with other risk factors for these events. In general, the risk is greatest among older (>35 years of age), hypertensive women who also smoke. Use CHCs with caution in women with cardiovascular disease risk factors. Figure 1 Figure 2 5.2 PK Profile of Ethinyl Estradiol The PK profile for the ORTHO EVRA patch is different from the PK profile for oral contraceptives in that it has a higher C ss and a lower C max . AUC and average C ss for EE are approximately 60% higher in women using ORTHO EVRA compared with women using an oral contraceptive containing EE 35 mcg. In contrast, the C max for EE is approximately 25% lower in women using ORTHO EVRA. Inter-subject variability results in increased exposure to EE in some women using either ORTHO EVRA or oral contraceptives. However, inter-subject variability in women using ORTHO EVRA is higher. It is not known whether there are changes in the risk of serious adverse events based on the differences in PK profiles of EE in women using ORTHO EVRA compared with women using oral contraceptives containing 30–35 mcg of EE. Increased estrogen exposure may increase the risk of adverse events, including venous thromboembolism. [see Boxed Warning and Clinical Pharmacology (12.3) .] 5.3 Liver Disease Impaired Liver Function Do not use ORTHO EVRA in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver [see Contraindications (4) ] . Discontinue ORTHO EVRA if jaundice develops. Acute or chronic disturbances of liver function may necessitate the discontinuation of CHC use until markers of liver function return to normal and CHC causation has been excluded. Liver Tumors ORTHO EVRA is contraindicated in women with benign and malignant liver tumors [see Contraindications (4) ] . Hepatic adenomas are associated with CHC use. An estimate of the attributable risk is 3.3 cases/100,000 CHC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) CHC users. However, the risk of liver cancers in CHC users is less than one case per million users. 5.4 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications, such as CHCs. Discontinue ORTHO EVRA prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4) ] . ORTHO EVRA can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen. 5.5 High Blood Pressure ORTHO EVRA is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see Contraindications (4) ] . For women with well-controlled hypertension, monitor blood pressure and stop ORTHO EVRA if blood pressure rises significantly. An increase in blood pressure has been reported in women taking hormonal contraceptives, and this increase is more likely in older women with extended duration of use. The incidence of hypertension increases with increasing concentrations of progestin. 5.6 Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among CHC users. Use of CHCs may also worsen existing gallbladder disease. A past history of CHC-related cholestasis predicts an increased risk with subsequent CHC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for CHC-related cholestasis. 5.7 Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who take ORTHO EVRA. CHCs may decrease glucose tolerance in a dose-related fashion. In a 6-cycle clinical trial with ORTHO EVRA there were no clinically significant changes in fasting blood glucose from baseline to end of treatment. Consider alternative contraception for women with uncontrolled dyslipidemia. A small proportion of women will have adverse lipid changes while on hormonal contraceptives. Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using hormonal contraceptives. 5.8 Headache If a woman taking ORTHO EVRA develops new headaches that are recurrent, persistent or severe, evaluate the cause and discontinue ORTHO EVRA if indicated. Consider discontinuation of ORTHO EVRA in the case of increased frequency or severity of migraine during hormonal contraceptive use (which may be prodromal of a cerebrovascular event). 5.9 Bleeding Irregularities Unscheduled Bleeding and Spotting Unscheduled (breakthrough) bleeding and spotting sometimes occur in women using ORTHO EVRA. Consider non-hormonal causes and take adequate diagnostic measures to rule out malignancy, other pathology, or pregnancy in the event of unscheduled bleeding, as in the case of any abnormal vaginal bleeding. If pathology and pregnancy have been excluded, time or a change to another contraceptive product may resolve the bleeding. In the clinical trials, most women started their scheduled (withdrawal) bleeding on the fourth day of the drug-free interval, and the median duration of withdrawal bleeding was 5 to 6 days. On average, 26% of women per cycle had 7 or more total days of bleeding and/or spotting (this includes both scheduled and unscheduled bleeding and/or spotting). Three clinical studies of the efficacy of ORTHO EVRA in preventing pregnancy assessed scheduled and unscheduled bleeding [see Clinical Studies (14) ] in 3,330 women who completed 22,155 cycles of exposure. A total of 36 (1.1%) of the women discontinued ORTHO EVRA at least in part, due to bleeding or spotting. Table 2 summarizes the proportion of subjects who experienced unscheduled (breakthrough) bleeding/spotting by treatment cycle. Table 2: Unscheduled (Breakthrough) Bleeding/Spotting (Subjects Evaluable for Efficacy) Treatment Cycle Pooled data from 3 studies N=3319 n % Percentage of subjects with breakthrough bleeding/spotting events. Cycle 1 2994 18.2 Cycle 2 2743 11.9 Cycle 3 2699 11.6 Cycle 4 2541 10.1 Cycle 5 2532 9.2 Cycle 6 2494 8.3 Cycle 7 698 8.3 Cycle 8 692 8.7 Cycle 9 654 8.6 Cycle 10 621 8.7 Cycle 11 631 8.9 Cycle 12 617 6.3 Cycle 13 611 8.0 Amenorrhea and Oligomenorrhea In the event of amenorrhea, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one patch or started the patch on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. Some women may encounter amenorrhea or oligomenorrhea after discontinuation of hormonal contraceptive use, especially when such a condition was pre-existent. 5.10 Hormonal Contraceptive Use Before or During Early Pregnancy Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. Discontinue ORTHO EVRA use if pregnancy is confirmed. Administration of CHCs should not be used as a test for pregnancy [see Use in Specific Populations (8.1) ]. 5.11 Depression Carefully observe women with a history of depression and discontinue ORTHO EVRA if depression recurs to a serious degree. 5.12 Carcinoma of Breasts and Cervix ORTHO EVRA is contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4) ] . There is substantial evidence that CHCs do not increase the incidence of breast cancer. Although some past studies have suggested that CHCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings. Some studies suggest that combination oral contraceptive use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. 5.13 Effect on Binding Globulins The estrogen component of CHCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased. 5.14 Monitoring A woman who is taking hormonal contraceptive should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare. 5.15 Hereditary Angioedema In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. 5.16 Chloasma Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while using ORTHO EVRA.

<table width="75%" ID="table1"> <caption>Table 1: Estimates (Risk Ratios) of Venous Thromboembolism Risk in Current Users of ORTHO EVRA Compared to Combined Oral Contraceptive Users</caption> <col width="35%" align="center" valign="middle"/> <col width="25%" align="center" valign="middle"/> <col width="40%" align="center" valign="middle"/> <thead> <tr> <th styleCode="Lrule Rrule">Epidemiologic Study<footnote>&quot;New users&quot; &#x2013; i.e., women with no prior exposure to the drug studied during a pre-specified time period &#x2013; are considered to be the most informative population to study in pharmacoepidemiologic safety studies. All estimates took account of new-user status. The method and time period used to identify &quot;new users&quot; varied from study to study.</footnote> </th> <th styleCode="Rrule">Comparator Product</th> <th styleCode="Rrule">Risk Ratios (95% CI)</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">i3 Ingenix NGM Study in Ingenix Research Datamart^1,6,7,8 </td> <td styleCode="Rrule">NGM/35 mcg EE<footnote>NGM = norgestimate; EE = ethinyl estradiol</footnote> </td> <td styleCode="Rrule"> <content styleCode="bold">2.2</content> <footnote ID="t1fc">Increase in risk of VTE is statistically significant</footnote> <content styleCode="bold"> (1.2&#x2013;4.0)<footnote>Pooled risk ratio from references 1 and 6 covering the initial 33-month study plus 24-month extension. [Initial 33 months of data: Risk Ratio (95% CI) = 2.5^C (1.1&#x2013;5.5); Separate estimate from the 24 months of data on new cases not included in the previous estimate: Risk Ratio (95% CI) = 1.4 (0.5&#x2013;3.7)]. These risk ratios are based on idiopathic cases (those in women without other known risk factors for VTE). If all VTE cases are considered, the pooled risk ratio and 95% CI are 2.0 (1.2&#x2013;3.3)^C.</footnote> </content> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">BCDSP<footnote ID="t1fe">BCDSP = Boston Collaborative Drug Surveillance Program; the risk ratios are based on idiopathic cases.</footnote> NGM Study in Pharmetrics database^2,3,5 </td> <td styleCode="Rrule">NGM/35 mcg EE</td> <td styleCode="Rrule"> <content styleCode="bold">1.2 (0.9&#x2013;1.8)<footnote>Pooled risk ratio from references 2, 3 and 5 covering the initial 36-month study, plus 17-month and 14-month extensions. [Initial 36 months of data: Risk Ratio (95% CI) = 0.9 (0.5&#x2013;1.6); Separate estimate from 17 months of data on new cases not included in the previous estimate: Risk Ratio (95% CI) = 1.1 (0.6&#x2013;2.1); Separate estimate from 14 months of data on new cases not included in the previous estimates: Risk Ratio (95% CI) = 2.4^C (1.2&#x2013;5.0)]</footnote> </content> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">BCDSP<footnoteRef IDREF="t1fe"/> LNG Study in Pharmetrics database⁴ </td> <td styleCode="Rrule">LNG<footnote>LNG = levonorgestrel</footnote>/30 mcg EE</td> <td styleCode="Rrule"> <content styleCode="bold">2.0 (0.9&#x2013;4.1)<footnote>48 months of data.</footnote> </content> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">BCDSP<footnoteRef IDREF="t1fe"/> LNG Study in Marketscan database⁴ </td> <td styleCode="Rrule">LNG/30 mcg EE</td> <td styleCode="Rrule"> <content styleCode="bold">1.3 (0.8&#x2013;2.1)<footnote>69 months of data.</footnote> </content> </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule" rowspan="2" align="left">FDA-funded Study in Kaiser Permanente and Medicaid databases<footnote>84 months of data in FDA-funded study</footnote> ^, <footnote>Results for &quot;All users,&quot; i.e., initiation and continuing use of study combination hormonal contraception: &quot;All progestins&quot;/20&#x2013;35 mcg EE, Risk Ratio (95% CI) = 1.6 (1.2&#x2013;2.1)^C and LNG/30 mcg EE, Risk Ratio (95% CI) = 1.3 (1.0&#x2013;1.8).</footnote> ^{, 9} </td> <td styleCode="Rrule">&quot;All progestins<footnote>Includes the following progestins: LNG, norethindrone, norgestimate.</footnote>&quot;/20&#x2013;35 mcg EE</td> <td styleCode="Rrule"> <content styleCode="bold">1.4 (0.9&#x2013;2.0)</content> </td> </tr> <tr> <td styleCode="Rrule">LNG/ 30 mcg EE</td> <td styleCode="Rrule"> <content styleCode="bold">1.2 (0.8&#x2013;1.9)</content> </td> </tr> </tbody> </table>

<table width="75%" ID="table2"> <caption>Table 2: Unscheduled (Breakthrough) Bleeding/Spotting (Subjects Evaluable for Efficacy)</caption> <col width="34%" align="left" valign="top"/> <col width="33%" align="center" valign="top"/> <col width="33%" align="center" valign="top"/> <thead> <tr styleCode="Botrule"> <th>Treatment Cycle</th> <th colspan="2">Pooled data from 3 studies N=3319</th> </tr> <tr> <th/> <th>n</th> <th>%<footnote>Percentage of subjects with breakthrough bleeding/spotting events.</footnote> </th> </tr> </thead> <tbody> <tr> <td>Cycle 1</td> <td>2994</td> <td>18.2</td> </tr> <tr> <td>Cycle 2</td> <td>2743</td> <td>11.9</td> </tr> <tr> <td>Cycle 3</td> <td>2699</td> <td>11.6</td> </tr> <tr> <td>Cycle 4</td> <td>2541</td> <td>10.1</td> </tr> <tr> <td>Cycle 5</td> <td>2532</td> <td>9.2</td> </tr> <tr> <td>Cycle 6</td> <td>2494</td> <td>8.3</td> </tr> <tr> <td>Cycle 7</td> <td>698</td> <td>8.3</td> </tr> <tr> <td>Cycle 8</td> <td>692</td> <td>8.7</td> </tr> <tr> <td>Cycle 9</td> <td>654</td> <td>8.6</td> </tr> <tr> <td>Cycle 10</td> <td>621</td> <td>8.7</td> </tr> <tr> <td>Cycle 11</td> <td>631</td> <td>8.9</td> </tr> <tr> <td>Cycle 12</td> <td>617</td> <td>6.3</td> </tr> <tr> <td>Cycle 13</td> <td>611</td> <td>8.0</td> </tr> </tbody> </table>

6 ADVERSE REACTIONS The following serious adverse reactions with the use of combination hormonal contraceptives, including ORTHO EVRA, are discussed elsewhere in the labeling: Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions (5.1) ] Vascular events, including venous and arterial thromboembolic events [see Warnings and Precautions (5.1) ] Liver disease [see Warnings and Precautions (5.3) ] Adverse reactions commonly reported by users of combination hormonal contraceptives are: Irregular uterine bleeding Nausea Breast tenderness Headache The most frequent adverse reactions reported during clinical trials (≥ 5%) were breast symptoms, nausea/vomiting, headache, application site disorder, abdominal pain, dysmenorrhea, vaginal bleeding and menstrual disorders, and mood, affect and anxiety disorders. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The data described below reflect exposure to ORTHO EVRA in 3330 sexually active women (3322 of whom had safety data) who participated in three Phase 3 clinical trials designed to evaluate contraceptive efficacy and safety. These subjects received six or 13 cycles of contraception (ORTHO EVRA or an oral contraceptive comparator in 2 of the trials). The women ranged in age from 18 to 45 years and were predominantly white (91%). The most common adverse reactions (≥ 5%) reported during clinical trials were breast symptoms, nausea/vomiting, headache, application site disorder, abdominal pain, dysmenorrhea, vaginal bleeding and menstrual disorders, and mood, affect and anxiety disorders. The most common events leading to discontinuation were application site reaction, breast symptoms (including breast discomfort, engorgement and pain), nausea and/or vomiting, headache and emotional lability. Adverse drug reactions reported by ≥ 2.5% of ORTHO EVRA-treated subjects in these trials are shown in Table 3. Table 3: Adverse Drug Reactions Reported by ≥ 2.5% of ORTHO EVRA-treated Subjects in Three Phase 3 Clinical Trials System/Organ Class MedDRA version 10.0 Adverse reaction ORTHO EVRA (n=3322) Reproductive system and breast disorders Breast symptoms Represents a bundle of similar terms 22.4% Dysmenorrhea 7.8% Vaginal bleeding and menstrual disorders 6.4% Gastrointestinal disorders Nausea 16.6% Abdominal pain 8.1% Vomiting 5.1% Diarrhea 4.2% Nervous system disorders Headache 21.0% Dizziness 3.3% Migraine 2.7% General disorders and administration site conditions Application site disorder 17.1% Fatigue 2.6% Psychiatric disorders Mood, affect and anxiety disorders 6.3% Skin and subcutaneous tissue disorders Acne 2.9% Pruritus 2.5% Infections and infestations Vaginal yeast infection 3.9% Investigations Weight increased 2.7% Additional adverse drug reactions that occurred in < 2.5% of ORTHO EVRA-treated subjects in the above clinical trials datasets are: Gastrointestinal disorders: Abdominal distension General disorders and administration site conditions: Fluid retention 1 , malaise Hepatobiliary disorders: Cholecystitis Investigations: Blood pressure increased, lipid disorders Represents a bundle of similar terms Musculoskeletal and connective tissue disorders: Muscle spasms Psychiatric disorders: Insomnia, libido decreased, libido increased Reproductive system and breast disorders: Galactorrhea, genital discharge, premenstrual syndrome, uterine spasm, vaginal discharge, vulvovaginal dryness Respiratory, thoracic and mediastinal disorders: Pulmonary embolism Skin and subcutaneous tissue disorders: Chloasma, dermatitis contact, erythema, skin irritation 6.2 Postmarketing Experience The following adverse reactions (Table 4) have been identified during post-approval use of ORTHO EVRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Table 4: Alphabetical List of Adverse Drug Reactions Identified During Postmarketing Experience with ORTHO EVRA/EVRA by System Organ Class MedDRA version 10.0 System Organ Class Adverse Drug Reactions Cardiac disorders Myocardial infarction Represents a bundle of similar terms Endocrine disorders Hyperglycemia, insulin resistance Eye disorders Contact lens intolerance or complication Gastrointestinal disorders Colitis General disorders and administration site conditions Application site reaction , edema Hepatobiliary disorders Blood cholesterol abnormal, cholelithiasis, cholestasis, hepatic lesion, jaundice cholestatic, low density lipoprotein increased Immune system disorders Allergic reaction , urticaria Investigations Blood glucose abnormal, blood glucose decreased Metabolism and nutrition disorders Increased appetite Neoplasms benign, malignant and unspecified (Incl. cysts and polyps) Breast cancer , cervix carcinoma, hepatic adenoma, hepatic neoplasm Nervous system disorders Dysgeusia, migraine with aura Psychiatric disorders Anger, emotional disorder, frustration, irritability Reproductive system and breast disorders Breast mass, cervical dysplasia, fibroadenoma of breast, menstrual disorder , suppressed lactation, uterine leiomyoma Skin and subcutaneous tissues disorders Alopecia, eczema, erythema multiforme, erythema nodosum, photosensitivity reaction, pruritus generalized, rash , seborrheic dermatitis, skin reaction Vascular disorders Arterial thrombosis , cerebrovascular accident , deep vein thrombosis , hemorrhage intracranial , hypertension, hypertensive crisis, pulmonary embolism , thrombosis

<table width="75%" ID="table3"> <caption>Table 3: Adverse Drug Reactions Reported by &#x2265; 2.5% of ORTHO EVRA-treated Subjects in Three Phase 3 Clinical Trials</caption> <col width="75%" align="left" valign="top"/> <col width="25%" align="center" valign="top"/> <thead> <tr> <th styleCode="Lrule Rrule">System/Organ Class<footnote>MedDRA version 10.0</footnote> Adverse reaction</th> <th styleCode="Rrule">ORTHO EVRA (n=3322)</th> </tr> </thead> <tbody> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold">Reproductive system and breast disorders</content> </td> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule">Breast symptoms<footnote ID="t3f1">Represents a bundle of similar terms</footnote> </td> <td styleCode="Rrule">22.4%</td> </tr> <tr> <td styleCode="Lrule Rrule">Dysmenorrhea</td> <td styleCode="Rrule">7.8%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Vaginal bleeding and menstrual disorders<footnoteRef IDREF="t3f1"/> </td> <td styleCode="Rrule">6.4%</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold">Gastrointestinal disorders</content> </td> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule">Nausea</td> <td styleCode="Rrule">16.6%</td> </tr> <tr> <td styleCode="Lrule Rrule">Abdominal pain<footnoteRef IDREF="t3f1"/> </td> <td styleCode="Rrule">8.1%</td> </tr> <tr> <td styleCode="Lrule Rrule">Vomiting</td> <td styleCode="Rrule">5.1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Diarrhea</td> <td styleCode="Rrule">4.2%</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold">Nervous system disorders</content> </td> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule">Headache</td> <td styleCode="Rrule">21.0%</td> </tr> <tr> <td styleCode="Lrule Rrule">Dizziness</td> <td styleCode="Rrule">3.3%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Migraine</td> <td styleCode="Rrule">2.7%</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold">General disorders and administration site conditions</content> </td> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule">Application site disorder<footnoteRef IDREF="t3f1"/> </td> <td styleCode="Rrule">17.1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Fatigue</td> <td styleCode="Rrule">2.6%</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold">Psychiatric disorders</content> </td> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Mood, affect and anxiety disorders<footnoteRef IDREF="t3f1"/> </td> <td styleCode="Rrule">6.3%</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold">Skin and subcutaneous tissue disorders</content> </td> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule">Acne</td> <td styleCode="Rrule">2.9%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Pruritus</td> <td styleCode="Rrule">2.5%</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold">Infections and infestations</content> </td> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Vaginal yeast infection<footnoteRef IDREF="t3f1"/> </td> <td styleCode="Rrule">3.9%</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold">Investigations</content> </td> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule">Weight increased</td> <td styleCode="Rrule">2.7%</td> </tr> </tbody> </table>

<table width="75%" ID="table4"> <caption>Table 4: Alphabetical List of Adverse Drug Reactions Identified During Postmarketing Experience with ORTHO EVRA/EVRA by System Organ Class<footnote>MedDRA version 10.0</footnote> </caption> <col width="50%" align="left" valign="top"/> <col width="50%" align="left" valign="top"/> <thead> <tr> <th align="center">System Organ Class</th> <th align="center">Adverse Drug Reactions</th> </tr> </thead> <tbody> <tr> <td> <content styleCode="bold">Cardiac disorders</content> </td> <td>Myocardial infarction<footnote ID="t4f1">Represents a bundle of similar terms</footnote> </td> </tr> <tr> <td> <content styleCode="bold">Endocrine disorders</content> </td> <td>Hyperglycemia, insulin resistance</td> </tr> <tr> <td> <content styleCode="bold">Eye disorders</content> </td> <td>Contact lens intolerance or complication</td> </tr> <tr> <td> <content styleCode="bold">Gastrointestinal disorders</content> </td> <td>Colitis</td> </tr> <tr> <td> <content styleCode="bold">General disorders and administration site conditions</content> </td> <td>Application site reaction<footnoteRef IDREF="t4f1"/>, edema<footnoteRef IDREF="t4f1"/> </td> </tr> <tr> <td> <content styleCode="bold">Hepatobiliary disorders</content> </td> <td>Blood cholesterol abnormal, cholelithiasis, cholestasis, hepatic lesion, jaundice cholestatic, low density lipoprotein increased</td> </tr> <tr> <td> <content styleCode="bold">Immune system disorders</content> </td> <td>Allergic reaction<footnoteRef IDREF="t4f1"/>, urticaria</td> </tr> <tr> <td> <content styleCode="bold">Investigations</content> </td> <td>Blood glucose abnormal, blood glucose decreased</td> </tr> <tr> <td> <content styleCode="bold">Metabolism and nutrition disorders</content> </td> <td>Increased appetite</td> </tr> <tr> <td> <content styleCode="bold">Neoplasms benign, malignant and unspecified (Incl. cysts and polyps)</content> </td> <td>Breast cancer<footnoteRef IDREF="t4f1"/>, cervix carcinoma, hepatic adenoma, hepatic neoplasm</td> </tr> <tr> <td> <content styleCode="bold">Nervous system disorders</content> </td> <td>Dysgeusia, migraine with aura</td> </tr> <tr> <td> <content styleCode="bold">Psychiatric disorders</content> </td> <td>Anger, emotional disorder, frustration, irritability</td> </tr> <tr> <td> <content styleCode="bold">Reproductive system and breast disorders</content> </td> <td>Breast mass, cervical dysplasia, fibroadenoma of breast, menstrual disorder<footnoteRef IDREF="t4f1"/>, suppressed lactation, uterine leiomyoma</td> </tr> <tr> <td> <content styleCode="bold">Skin and subcutaneous tissues disorders</content> </td> <td>Alopecia, eczema, erythema multiforme, erythema nodosum, photosensitivity reaction, pruritus generalized, rash<footnoteRef IDREF="t4f1"/>, seborrheic dermatitis, skin reaction</td> </tr> <tr> <td> <content styleCode="bold">Vascular disorders</content> </td> <td>Arterial thrombosis<footnoteRef IDREF="t4f1"/>, cerebrovascular accident<footnoteRef IDREF="t4f1"/>, deep vein thrombosis<footnoteRef IDREF="t4f1"/>, hemorrhage intracranial<footnoteRef IDREF="t4f1"/>, hypertension, hypertensive crisis, pulmonary embolism<footnoteRef IDREF="t4f1"/>, thrombosis<footnoteRef IDREF="t4f1"/> </td> </tr> </tbody> </table>